tbuckley/cabot-search huggingface dataset:
Predictive biomarkers for response to immunotherapy in patients with deficient DNA mismatch repair metastatic colorectal cancer.
Authors: Amos Stemmer, Gal Strauss, Naama Halpern, Tamar Beller, Talya Golan, Ofer Margalit, Einat Shacham-Shmueli, Ben Boursi
Journal: Journal of Clinical Oncology (2023)

254 Background: Deficient DNA mismatch repair (MMRD) accounts for approximately 3% of metastatic colorectal cancers (mCRC). Treatment with Immune checkpoint inhibitors (ICI) in this patient population achieve an overall response rate (ORR) of up to 55%. However, to date there are no predictive biomarkers for response. Methods: A retrospective analysis of all MMRD mCRC patients that were treated with either Pembrolizumab, or Ipilimumab and Nivolumab in a large tertiary medical center between 2015-2022. The primary outcome was response to treatment and was assessed at first imaging following treatment initiation. Exposure variables included age, sex, ECOG performance status, metastatic sites (liver, peritoneum, lung, bone and brain) and CEA levels at treatment initiation. CEA below 5 mcg/l was treated as low and above as high CEA levels. Predictive biomarkers were assessed using cox hazard regression and Kaplan Meier analysis. Results: A total of 33 prospective MMRD mCRC patients were included in the study. Of them, 24 (72.7%) responded and 9 (27.3%) did not respond to immunotherapy. Median age was 70 (IQR 66-77) and 64 (IQR 51-75) for responders and non-responders respectively. Site of metastasis was an important predictor for response. Thirteen patients had liver metastasis, of them 6 (46%) responded (HR = 7.16; 95% CI = 1.47-35; p = 0.015). Five patients had single site metastasis in the liver, of them one (20%) responded (HR = 12.7; 95% CI = 2.99-53.8; p &lt; 0.001). Fifteen patients had peritoneal metastasis, of them 13 (87%) responded to treatment (HR = 0.24; 95% CI = 0.05-1.19; p = 0.081). Median CEA at treatment initiation was 2 (IQR 1-4) in responders compared to 32 (IQR 1-70) for non-responders (HR = 5.27; 95% CI = 1.31-21.2; p = 0.019). There was no statistically significant difference between the groups in age, sex and ECOG performance status. Conclusions: Liver metastasis predict poor response to immunotherapy in MMRD mCRC patients while peritoneal metastasis and low CEA level predict response to immunotherapy.
A phase 1b, open-label, safety, pharmacokinetic, and pharmacodynamic study of an anti–super-enhancer triptolide analogue with <i>nab</i>-paclitaxel plus gemcitabine in patients with metastatic adenocarcinoma of the pancreas.
Authors: Joon Oh Park, Jung Yong Hong, Seung Tae Kim, Young Suk Park, Ashok Saluja
Journal: Journal of Clinical Oncology (2023)

TPS769 Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies and the leading cause of cancer-related death in the world, although recent advances in chemotherapies for metastatic PDAC provide better clinical outcomes. Triptolide (TPL), a natural compound isolated from the Chinese herb has shown promising antitumor activity though the inhibition of HSP70 in a number of preclinical models including pancreatic cancer. In addition, TPL disrupt super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts to reprogram the cellular cross talk and signaling in tumor environment. Minnelide (ML), water soluble, novel prodrug of TPL, was recently reported to show promising activity in patients with gastrointestinal malignancies in phase I trial. Based on the strong synergism with nab-paclitaxel (A) plus gemcitabine (G), we designed this phase 1b study. Methods: Eligible patients will have histologically confirmed PDAC and have failed first-line FOLFIRINOX with adequate organ function and performance status. This study is composed of two parts; dose escalation and dose expansion. In the dose escalation part (phase 1b), different dose levels of ML (0.25 mg to 1.0 mg once a day) in combination with A plus G will be tested with 3+3 subjects recruited in each cohort. Patients in each cohort will receive ML 0.25 to 1.0 mg orally once a day on days 1-5, 8-12 and 15-19 with A 100-125mg/m 2 intravenously plus G 800-1000mg/m 2 IV on days 1, 8 &amp; 15 of a 28-day cycle. The primary endpoint is to determine the safety of ML with A+G and to determine PFS by Independent Radiological Review (IRR). Once an MTD reaches, a total of 18 patients will be enrolled at MTD level in dose expansion part. The key secondary endpoints are to determine the pharmacokinetics, pharmacodynamics effect, the percentage of patients who achieve an objective confirmed overall response by IRR, maximum tolerated dose and recommended dose for phase 2 of ML in combination of A+G. As of September 2022, the study is just initiated for patient enrollment in first cohort. This study is prospectively registered on ClinicalTrials.gov, NCT05557851. Clinical trial information: NCT05557851 .
Nivolumab (NIVO) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 3-year follow-up from CheckMate 649.
Authors: Yelena Y. Janjigian, Kohei Shitara, Markus H. Moehler, Marcelo Garrido, Carlos Gallardo, Lin Shen, Kensei Yamaguchi, Lucjan Wyrwicz, Tomasz Skoczylas, Arinilda Silva Campos Bragagnoli, Tianshu Liu, Mustapha Tehfe, Elena Elimova, Ricardo Elias Bruges Maya, James M. Cleary, Michalis Karamouzis, Samira Soleymani, Ming Lei, Carlos Amaya-Chanaga, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2023)

291 Background: NIVO + chemo demonstrated superior overall survival (OS) and clinically meaningful progression-free survival (PFS) benefit vs chemo and an acceptable safety profile in previously untreated patients (pts) with advanced GC/GEJC/EAC, leading to approvals in multiple countries including the US. NIVO + chemo continued to demonstrate clinically meaningful improvement in efficacy after 2 years of follow-up. We present efficacy and safety analyses from NIVO + chemo vs chemo from the 3-year follow-up of CheckMate 649. Methods: Adults with previously untreated, unresectable advanced, or metastatic GC/GEJC/EAC were enrolled, regardless of programmed death ligand 1 (PD-L1) expression. Pts with known HER2-positive status were excluded. Randomized pts received NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 581 pts were concurrently randomized to NIVO + chemo or chemo. With 36-month (mo) minimum follow-up, NIVO + chemo continued to demonstrate OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5 and all randomized pts. The objective response rate (ORR) per BICR in pts with PD-L1 CPS ≥ 5 who had measurable lesions at baseline was 60% (95% CI 55–65) with NIVO + chemo vs 45% (95% CI 40–50) with chemo; in all randomized pts, ORR per BICR was 58% (95% CI 54–62) with NIVO + chemo vs 46% (95% CI 42–50) with chemo. Responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5 (median [m] duration of response [mDOR] 9.6 mo [95% CI 8.2–12.4] vs 7.0 mo [95% CI 5.6–7.9], respectively) and in all randomized pts (mDOR 8.5 mo [95% CI 7.7–9.9] vs 6.9 mo [95% CI 5.8–7.2], respectively). OS benefit with NIVO + chemo was observed across most prespecified subgroups. No new safety signals were identified. A summary of treatment-related adverse events (TRAEs) is shown here. Conclusions: After 3 years of follow-up, NIVO + chemo continued to demonstrate clinically meaningful long-term survival benefit with an acceptable safety profile, further supporting its use as a standard 1L treatment in previously untreated pts with advanced GC/GEJC/EAC. Clinical trial information: NCT02872116 . [Table: see text]
Characteristics of immune-infiltrating cells in the tumor microenvironment of appendiceal cancer with peritoneal disease.
Authors: Madeleine Cornelia Strach, Nicole Yeung, Hui-Ming Lin, Nabila Ansari, Cherry Koh, Joo-Shik Shin, James Kench, Lisa Horvath, Kate Lynette Mahon
Journal: Journal of Clinical Oncology (2023)

217 Background: Appendiceal cancers (AC) are rare, associated with peritoneal metastases, and respond poorly to current systemic treatments. There are limited studies on the characteristics and prognostic impact of infiltrating immune cells within the tumour microenvironment (TME) of AC with peritoneal metastases. Infiltrating immune cells are associated with survival outcomes and predict the effectiveness of immunotherapies in solid tumours. Different definitions have been developed to describe infiltrating immune cells and associated structures such as tertiary lymphoid aggregates (TLS). The aim of our study was to describe the immune TME in patients with AC peritoneal metastases to understand mechanisms of sensitivity and resistance to chemoimmunotherapies. Methods: Fresh tissue was collected during cytoreductive surgery from consenting patients with AC with peritoneal disease (Jul 2020-Feb 2022). Uncultured Day 0 tissues were fixed in formalin prior to paraffin embedding (FFPE). Haematoxylin and eosin (H&amp;E) staining was performed on sections of FFPE tissue. Sections were evaluated by light microscopy for the presence of immune cells based on morphological appearance. Patterns of infiltrating immune cells were classified based on location (peritumoural, intratumoural, perimucinous, stromal), and aggregation (none, immature, mature). Immune cells forming aggregates were counted and the diameter of aggregates measured using QuPath. Results: We evaluated 25 patients with AC peritoneal disease during the study period. Immune cells were detected in tissues from all except 3 patients; 16 cases (78 immune areas) were low grade (LG) disease of primary appendiceal mucinous neoplasms, and 6 cases (29 immune areas) were high grade (HG) from primary appendiceal adenocarcinomas (Table). Immune cell aggregates had a median diameter of 209 mm (75-491) and median cell count of 892 cells (46-6490). Conclusions: This study represents the first formal description and characterisation of infiltrating immune cells in appendiceal cancer peritoneal metastases. Perimucinous immune cells were not observed in HG disease despite presence of mucin. Intratumoural immune cells were not observed in LG disease, consistent with these tumours being more resistant to chemotherapy. We plan ongoing work correlating the immune features with clinical outcomes alongside immunohistochemical and transcriptomic characterisation of the aggregates. [Table: see text]
Impact of infiltrating T cell subtypes on survival and response to FLOT chemotherapy in resectable oesophagogastric adenocarcinoma (OGA).
Authors: Avani Athauda, Tatiany Silveira, Thomas Lund, Katharina von Loga, Benjamin Challoner, Isma Rana, Janet Thomas, Naureen Starling, Ian Chau, Sheela Rao, David J. Watkins, David Cunningham, Marco Gerlinger
Journal: Journal of Clinical Oncology (2023)

443 Background: The prognostic and predictive relevance of tumour infiltrating T cell subtypes and of PD-L1 expression in localised OGA treated with FLOT chemotherapy (CTx) and surgery is poorly understood. Methods: Pre-CTx biopsy tissue was retrospectively collected from 46 patients (pts) with localised OGA who received perioperative FLOT and underwent surgery at a single institution. Opal Multicolour immunofluorescence was performed with primary antibodies against CD4, CD8, FOXP3, CD45RO, PD-1 and cytokeratin. Digital image analysis was performed using inForm and HALO softwares. PD-L1 CPS was determined using the E1L3N clone and the standard CPS assessment algorithm (CPS≥5 = high; CPS &lt;5 = low). CTx responses were assessed according to Mandard Tumour Regression Grade (TRG). For each immune cell marker and T cell phenotype, high vs low groups were defined using median cell density (count/mm 2 ) as the cut-off. Association of high vs low cell density with disease free survival (DFS) was assessed using the log-rank test and correlation with pathological response to CTx was assessed using the Chi-squared test. The paired Wilcoxon rank-sum test was used to compare differences in immune cell densities between paired pre-CTx biopsy and post-CTx resection samples in a subset of 35 pts. Results: Pts with a PD-1+ cell density above median in biopsy had significantly longer DFS compared to those with a density below median (median DFS not reached vs 1111 days; HR 0.3, 95% CI 0.1 – 0.8; p=0.028). A trend towards longer survival was also observed in the CD8+ high, FOXP3+ high, and activated CD8+ (CD8+ PD-1+) high groups. There was no association between PD-L1 CPS, CD4+, CD45RO+, memory CD8+ (CD8+ CD45RO+), regulatory CD4+ (CD4+ FOXP3+), memory CD4+ (CD4+ FOXP3- CD45RO+), and activated CD4+ (CD4+ FOXP3- PD-1+) cells and survival. Pts with higher density of PD-1+ cells achieved better responses than those with low PD-1+ cells (TRG1/2 48% vs 9%, p=0.017). Pts with PD-L1 CPS ≥10 in biopsy were numerically more likely to achieve better responses to FLOT (46% TRG1/2). PD1+ cell density decreased in resection specimens in good CTx responders but did not differ in non-responders. FOXP3+ cells significantly decreased whereas CD45RO+ cells and memory CD8+ cells significantly increased in non-responders only. Conclusions: These results indicate prognostic and predictive value of PD-1 expressing tumour infiltrating T cells in resectable OGA treated with perioperative FLOT CTx. CD8+, activated CD8+ and FOXP3+ cells were associated with a trend in longer survival. This analysis provides candidate biomarkers for further study in larger cohorts on the association between infiltrating immune cells and prognosis as well as response to standard cytotoxic CTx in Western patients.
Phase I study of autologous transgenic T cells expressing high affinity mesothelin-specific T-cell receptor (TCR; FH-TCR T<sub>MSLN</sub>) in patients with metastatic pancreatic ductal adenocarcinoma (mPDA).
Authors: E. Gabriela Chiorean, Aude Chapuis, Andrew L. Coveler, Cecilia CS Yeung, Ted Gooley, David Bing Zhen, Gentry Teng King, Lindsay Marie Hannan, Stacey A. Cohen, Rachael A Safyan, Anthony Germani, Susan Ra, Jennifer Casserd, Thomas Schmitt, Philip D Greenberg
Journal: Journal of Clinical Oncology (2023)

TPS779 Background: PDA has a low tumor mutational burden and an immunosuppressive microenvironment. Targeting overexpressed self-antigens with adoptive, genetically engineered, high affinity T cells may overcome immunosuppression (Stromnes I, Immunol Rev 2014). We previously engineered murine CD8 + T cells to express a high affinity MSLN-specific TCR in the Kras LSL-G12D/+ ; Trp53 LSL-R172H/+ ; p48 Cre/+ ( KPC) mouse model, with highest efficacy observed following serial infusions (Stromnes I, Cancer Cell 2015). We developed an autologous TCR-T cell therapy targeting MSLN, which is overexpressed by 80% of PDAs. In this first-in-human phase I trial, we seek to determine the safety, preliminary efficacy, as well as the persistence, activation, localization, and functional capacity of FH-TCR T MSLN in chemotherapy refractory, MSLN + mPDA. Methods: Eligible pts have ECOG PS 0-1, ≥ 1 prior therapy for mPDA, life expectancy ≥ 12 wks, able/willing to undergo biopsies (at baseline, and after 3 and 6 wks of treatment), MSLN 2+ expression in ≥ 30% tumor cells by IHC, HLA-A*02:01, no HLA-B*13:02. Patients undergo leukapheresis, and approximately 3-4 weeks later, receive the first TCR-T MSLN cell infusion. Three TCR-T MSLN cell infusions given q21 days (d) are planned to be administered to each patient. Patients are enrolled in 4 cohorts by dose level (cohort 1: 1 x 10 9 ; cohort 2: 3.3 x 10 9 ; cohorts 3 and 4: 10 x 10 9 T cells), with a 3+3 design. Dose limiting toxicities (DLTs) are assessed during 21d after each TCR-T MSLN cells infusion. Lymphodepleting chemotherapy with fludarabine/cyclophosphamide is administered prior to the third TCR-T MSLN infusion (cohorts 1-3) or prior to the first TCR-T MSLN infusion (cohort 4). Primary endpoint is safety and DLTs. Secondary endpoints are ORR, PFS, OS. Exploratory endpoints are translational tumor and blood TCR-T MSLN cells biomarkers. Safety is assessed by CTCAE v5.0, with a goal of grade ≥ 3 TCR-T MSLN cells unexpected toxicity rate &lt;35%; stopping rate if toxicity is ≥20% is 0.06. Response is assessed by RECIST 1.1. Enrollment of 15 patients allows &gt;80% power to observe a statistically significant (one-sided alpha level 0.05), meaningful efficacy signal of ORR 20%. Secondary and exploratory endpoints will be descriptive and hypothesis generating. The study was activated in December 2021 and is open to accrual; 4 patients have been enrolled as of 24 Sept 2022. Clinical trial information: NCT04809766 .
DNA mismatch repair deficiency and outcomes of patients with resectable locally advanced gastric cancer treated with preoperative docetaxel, oxaliplatin, and S-1 plus surgery and postoperative S-1 or surgery and postoperative S-1: A sub-analysis of the phase 3 PRODIGY trial.
Authors: Jaewon Hyung, Young Soo Park, Hyungwoo Cho, Hyung-Don Kim, Min-Hee Ryu, Yoon-Koo Kang
Journal: Journal of Clinical Oncology (2023)

431 Background: Benefit of perioperative or postoperative chemotherapy for resectable locally advanced gastric cancer (LAGC) with DNA mismatch repair (MMR) deficiency is controversial due to concerns about the potential detrimental effect of perioperative chemotherapy. In this sub-analysis of the phase 3 PRODIGY trial, we evaluated the association between the MMR status and outcomes of resectable LAGC treated with perioperative or postoperative chemotherapy. Methods: Among 249 patients with resectable LAGC enrolled in the PRODIGY trial treated with either perioperative chemotherapy (preoperative docetaxel, oxaliplatin, and S-1 [DOS] followed by surgery and postoperative S-1; CSC arm) or surgery and postoperative S-1 (SC arm) at Asan Medical Center, those in the full analysis set with available tissue for MMR status assessment by immunohistochemistry were included in this study. Progression-free survival (PFS) was compared according to the MMR status and treatment arm. In the CSC arm, the pathologic complete response (pCR) rate was compared according to the MMR status. Results: A total of 231 patients (CSC arm, n = 108; SC arm, n = 123) were included in the study (median age, 58 years [range, 27–75]). Twenty-one patients (CSC arm, n = 8 [7.4%]; SC arm, n = 13 [10.6%]) had deficient MMR (D-MMR) tumors while the rest had proficient MMR (P-MMR) tumors. There was no significant difference in the baseline characteristics including the clinical stage according to the MMR status. Among patients with P-MMR tumors, PFS tended to be superior in the CSC arm than in the SC arm (hazard ratio [HR] 0.67 [95% confidence interval (CI) 0.44–1.03]; log-rank P = 0.07). Among patients with D-MMR tumors, the PFS of the CSC arm was not inferior to that of the SC arm (HR 0.50 [95% CI 0.10–2.60]; log-rank P = 0.41). In the CSC arm, the pCR rate was 5.0% (5/100) and 12.5% (1/8) in patients with P-MMR and D-MMR tumors, respectively. Conclusions: In this sub-analysis of the PRODIGY trial, the PFS of the CSC arm was not inferior to that of the SC arm among patients with D-MMR LAGC. Among patients who received preoperative DOS, the pCR rate was not lower in patients with D-MMR tumors compared with those with P-MMR tumors. Perioperative chemotherapy consisting of preoperative DOS followed by surgery and postoperative S-1 may be recommended for patients with LAGC regardless of the MMR status.
Long-term results from NRG-GI002: A phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC).
Authors: Thomas J. George, Greg Yothers, Osama E. Rahma, Theodore S. Hong, Marcia McGory Russell, Y. Nancy You, William Parker, Samuel A. Jacobs, Peter C. Lucas, Linda H. Colangelo, Marc J Gollub, William A. Hall, Lisa A. Kachnic, Madhuri Bajaj, Howard M. Gross, Richard A. Peterson, Jennifer Anne Dorth, Namrata Vijayvergia, Norman Wolmark
Journal: Journal of Clinical Oncology (2023)

7 Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel experimental arms (EAs) in LARC. EAs are not intended for direct comparison, but rather to concurrently randomized control arm (CA) patients. Primary endpoint (EP) and available secondary EPs (from EA1 using veliparib [V], PARPi; and EA2 using pembrolizumab [P], anti-PD-1) have been previously reported. We present long-term outcomes of all pts enrolled (NCT02921256). Methods: Stage II/III pts with MSS LARC (with any ONE of the following: distal location [cT3-4 ≤5cm from anal verge, any N]; bulky [any cT4 or tumor within 3mm of mesorectal fascia]; high risk for metastatic disease [cN2]; or not a sphincter-sparing surgery [SSS] candidate) were randomized to CA (neoadjuvant FOLFOX [x 4mo] → chemoRT [capecitabine with 50.4Gy] → surgery 8-12 wks later). EA1 added V (400mg PO BID) and EA2 added P (200mg IV Q3 wks x 6 doses) each concurrent with chemoRT. Primary EP: 4-point reduction in Neoadjuvant Rectal Cancer (NAR) score with a one-sided α=0.10, 80% power. NAR compared by linear model controlling for clinical T4 at entry (Y/N). Secondary EPs: OS, DFS. p-values are two-sided. Results: From 10/2016-2/2018, 178 pts were randomized (88 CA, 90 EA1). From 8/2018-5/2019, 185 pts were randomized (95 CA, 90 EA2). Baseline characteristics were previously reported. Median follow-up is 3.50 yrs for the 1 st comparison. Median follow-up is 3.15 yrs for the 2 nd comparison. Updated primary and long-term secondary outcomes are in the table. Conclusions: With longer follow-up, addition of V to TNT provided no significant differences in the NAR score or 3yr outcomes. The addition of P to TNT was associated with a statistically significant improvement in 3yr OS, but not DFS. Correlative molecular analyses are ongoing. Support: U10CA180868, -180822; UG1-189867; U24-196067; AbbVie; Merck. Clinical trial information: NCT02921256 . [Table: see text]